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The Journal of Neuroscience, July 21, 2004, 24(29):6590-6599; doi:10.1523/JNEUROSCI.5747-03.2004

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Development/Plasticity/Repair
Mood Stabilizer Valproate Promotes ERK Pathway-Dependent Cortical Neuronal Growth and Neurogenesis

Yanlei Hao,¹ Thomas Creson,¹ Lei Zhang,¹ Pipeng Li,¹ Fu Du,² Peixiong Yuan,¹ Todd D. Gould,¹ Husseini K. Manji,¹ and Guang Chen¹

¹Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-4405, and ²FD NeuroTechnologies, Ellicott City, Maryland 21041

Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.

Key words: valproate; ERK; neurite outgrowth; neurogenesis; mania; mood disorders

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Received Dec 30, 2003; revised June 1, 2004; accepted June 4, 2004.

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